Acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) is a major cause of sepsis-induced mortality in the ICU. Patients who initially survive may subsequently die with immune paralysis characterized by poorly understood mechanisms involving the over-expression of counter-regulatory cytokines that suppress NF-KB-dependent pro-Inflammatory cytokine synthesis. Sepsis induces heme oxygenase-1 (HO-1; Hmox1), which has specific anti-inflammatory effects, e.g. via carbon monoxide (CO) mediated IL-10 production, and exerts powerful control over the transcriptional network of mitochondrial biogenesis, which safeguards energy metabolism by improving mitochondrial mass and promoting clearance of damaged organelles {mitophagy). Our preliminary data demonstrate that HO-1/CO up-regulates the suppressor of cytokine signaling-3 (S0CS3), the inflammasome inhibitor/anti-apoptotic protein BCIXL, DNA damage regulated autophagy modulator protein 1 (Dram1), and the mitophagy genes NIX and BNIP3. This information suggests that the H0-1/C0 system links mitochondrial biogenesis, mitophagy, and counter inflammation through mechanisms involving S0CS3, BCIXL and Dram1. We hypothesize that the transcriptional network of mitochondrial biogenesis regulates the anti-inflammatory response through HO-1/CO-dependent NFE2I2 and NRF-1 activation, leading to up-regulation of IL10 and S0CS3, activation of mitophagy. and suppression of inflammasome-mediated IL-1 B production and suppression of apoptosis. Using Staphylococcal aureus (S. aureus) sepsis and pneumonia in mice and relevant cell models in two mechanistic molecular Aims, and through a translational third Aim, we will address how this integrated process of mitochondrial quality control mitigates lung and liver inflammation and hastens the resolution of sepsis. Completion of these Aims and a successful test of this hypothesis would allow a paradigm shift in our understanding and approach to sepsis-induced organ failure both experimentally and clinically, as well as test CO pre-clinically as a way to improve mitochondrial quality control in ALI and MODS.